Homocystinuria (Classic)
Overview
A deficiency of cystathionine beta-synthase (CBS) that results in the inability to degrade homocysteine to cystathionine, resulting in increased levels of homocysteine and methionine. A variant that represents a minority of cases is responsive to vitamin B6 (pyridoxine), but this type may be missed by newborn screening. Elevated homocysteine impairs the function of several proteins (including fibrillin), thereby interfering with the formation of disulfide bonds and impairing endothelial function. As a result, untreated patients are at significant risk for thromboembolic events, making up the leading cause of morbidity and early death in affected patients.Prenatal Testing
DNA testing by amniocentesis or chorionic villus sampling (CVS) if both disease-causing mutations of an affected family member have been identified.Clinical Characteristics
With treatment, normal IQ is possible. The reduction of thromboembolic events may decrease the incidence of other sequelae, such as ectopia lentis, seizures, and psychiatric problems as well.Without treatment, symptoms vary widely and may present at different ages, ranging from lens dislocation, poor vision, developmental delays, marfanoid habitus, and acute thromboembolism.
Initial symptoms in infants and toddlers may include:
- Developmental delay
- Emotional and behavioral challenges
- Thromboembolism
- Ectopia lentis (dislocation of the ocular lens) or severe myopia (nearsightedness)
- Marfanoid habitus: tall/ thin build; long fingers, arms, and legs
- Genu valgum (knock knees), pes cavus (high arch)
- Osteoporosis
- Decreased hair, skin, iris pigmentation
- Seizures
- Vascular disease and stroke
- Extrapyramidal signs (e.g., dystonia)
- Psychiatric abnormalities
- Intellectual disability
Follow-up Testing after Positive Screen
Obtain quantitative plasma amino acid analysis, total plasma homocysteine. Homocysteine measured on plasma amino acid analysis only measures free homocysteine, so a separate total homocysteine sample is necessary. Confirmed by markedly increased total homocysteine and methionine.It can also be confirmed by identifying biallelic pathogenic variants in CBS through genetic testing but is not always sensitive. Enzyme analysis of CBS activity may also be performed if genetic testing is indeterminant.
Primary Care Management
Upon Notification of the + Screen
- Contact the family and evaluate the infant for poor feeding or other problems.
- Urgent treatment is not likely to be needed in the newborn period, but patients should be referred immediately (see the ACT Sheet for Homocystinuria (ACMG) (
347 KB) for additional information).
- To confirm the diagnosis, work with the following service(s): Newborn Screening Services (see UT providers [3]).
- For evaluation and ongoing collaborative management, consult the following service(s): Pediatric Genetics (see UT providers [6]).
If the Diagnosis is Confirmed
- Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Homocystinuria - Information for Parents (STAR-G)).
- The geneticist may want to do a pyridoxine (B6) trial prior to starting treatment in order to evaluate B6 responsiveness.
- Assist in implementation and maintenance of a diet low in methionine and proteins.
- Provision of vitamin B6, betaine, vitamin B12, and methylfolate may be indicated.
- For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.
Specialty Care Collaboration
Initial consultation with the following service(s): Pediatric Genetics (see UT providers [6]) and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Obtain genetic counseling for the family. CBS enzyme replacement therapy is currently in preclinical phase, but participation in clinical trials may be available.Resources
Information & Support
For Professionals
Homocystinuria (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular
pathogenesis; from the University of Washington and the National Library of Medicine.
Disease InfoSearch for Homocystinuria (Genetic Alliance)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more.
Homocystinuria (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance
in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Utah Newborn Screening Program (UDOH)
Provides information about the program, related legislation, training for practices, and newborn conditions; Utah Department
of Health.
For Parents and Patients
Homocystinuria - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received
an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.
Homocystinuria (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources;
from the National Library of Medicine.
Tools
ACT Sheet for Homocystinuria (ACMG) ( 347 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical
Genetics.
Confirmatory Algorithms for Homocystinuria (ACMG) ( 209 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American
College of Medical Genetics.
Services for Patients & Families in Utah (UT)
| Service Categories | # of providers* in: | UT | NW | Other states (5) (show) | | ID | MT | NM | NV | RI |
|---|---|---|---|---|---|---|---|---|---|---|
| Newborn Screening Services | 3 | 1 | 22 | 4 | 1 | 2 | 1 | |||
| Pediatric Genetics | 6 | 1 | 3 | 7 | 4 | 4 | 4 | |||
For services not listed above, browse our Services categories or search our database.
* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.
Helpful Articles
PubMed search for homocystinuria and neonatal screening, last 5 years.
Mudd SH.
Hypermethioninemias of genetic and non-genetic origin: A review.
Am J Med Genet C Semin Med Genet.
2011;157(1):3-32.
PubMed abstract
Discusses briefly the genetic and non-genetic conditions that sometimes lead to abnormally elevated methionine. Focuses on
recent developments and differential diagnosis of hypermethioninemia.